Role of D-mannose in urinary tract infections – a narrative review

Prevalence

A WHO report from 2017 listed E. coli as the main species responsible for community- and hospital- acquired UTIs [6]. The WHO has recognized the matter as a high community and health-care burden. More than 150 million people are affected by UTIs annually [7, 8]. It is considered as one of the most common infections in communities as well as within healthcare settings. The prevalence of UTIs are especially high among women. An estimated 11% of women over the age of 18 suffer from UTI annually [9]. Approximately 50% of all women will have at least one UTI episode during their lifetime [10]. Women are at risk for UTI due to a short urethra located close to the rectum, which allows easier access for bacteria to the urinary tract as compared to men. Changes in the sexual activity, pregnancy, and menopausal status have a high impact on the risk for UTI occurrence since all of them affect the urogenital bacterial composition. Higher prevalence to UTI is also seen among specific populations such as people with structural changes (e.g. prostate enlargement) and diabetics (up to 35% of the patients) [11,12,13]. Moreover, healthcare-associated UTIs are the most common infections occurring in intensive-care units, especially among patients needing catheterization [14]. Furthermore, UTI is listed among the 10 most common reasons for unplanned readmission to medical care [15]. Therefore, the societal and healthcare costs caused by hospitalizations and medical expenses associated with UTI are high.

Diagnosis and etiology

UTIs can be categorized into several sub-classes based on their complexity, acuteness, and location [16]. Clinically, UTIs are classified as uncomplicated or complicated, where the first often considers otherwise healthy individuals and the latter is associated with structural or functional challenges e.g. pregnancy, male gender, young age (children), catheterization, or diabetes, which complicate the condition. UTI diagnosis can also be a recurrent UTI (rUTI) defined by the occurrence of more than 2 symptomatic UTIs within the last 6 months or more than 3 within the last 12 months. UTIs can be localized either in the upper urinary tract, including kidneys (upper UTI a.k.a. pyelonephritis), or on the lower urinary tract, affecting the bladder (lower UTI a.k.a. cystitis) [16].

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The gold standard for UTI diagnosis is based on pathogen detection and identification from a midstream urine sample (103-105 or more colony forming units (CFU)/ml urine) combined with clinical symptoms (dysuria, frequency, urgency, suprapubic pain, nocturia, and hematuria). In case the clinical symptoms are absent, and the number of bacteria counts exceed 105 CFU/ml, the diagnosis is asymptomatic bacteriuria and treatment is only rarely prescribed [17].

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UPEC is the main causative organism of UTIs, in both uncomplicated and complicated infections, being the responsible pathogen in up to 85% of the cases. Other pathogenic microbes associated with uncomplicated UTIs are, starting from the most likely pathogen, Klebsiella pneumoniae, Staphylococcus saprophyticus, Enterococcus faecalis, Group B Streptococcus (GBS), Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus as well as Candida species. Common pathogens associated with complicated UTIs are Enterococcus spp., K. pneumoniae, Candida spp., S. aureus, P. mirabilis, P. aeruginosa, and GBS [7].

Urinary microbiota and UTI

Advancements in molecular techniques have increased the understanding of the microbial community in the urinary tract, which has been previously regarded as sterile [18]. Overall, in contrast to the gut, urine contains very few microbes and is dominated by one or two species (also called as urotypes) [18, 19]. Research implies that the urinary microbiota is gender specific, likely due to anatomical and hormonal differences [20, 21]. As women are more at risk of UTI, we mainly focus on providing an overview of the urinary microbiota of women and association with UTI.

The most common bacteria in the urinary microbiota of healthy women are the same species of Lactobacillus that exists in the vagina [18, 22]. Other predominating species are from the genera Gardnerella, Streptococcus, Staphylococcus, Corynebacterium, and Escherichia. Research suggests that urotype changes with age and for instance a Lactobacillus- or Gardnerella-dominated urotype is in some cases reported to be more common in pre-menopausal women, whereas the Escherichia-dominated urotype and more diverse microbiota seem to predominate in postmenopausal women [18, 23].

Urinary microbiota is associated with rUTIs [24]. Especially changes resulting in the loss of normally protective Lactobacillus spp. seem to increase the risk of UTI. The vaginal tract is suggested to play a role in UTI pathogenesis by serving as a potential reservoir for uropathogenic bacteria ascending from the gastrointestinal tract. Studies show that women with rUTI have lower abundance of lactobacilli and are more commonly colonized with vaginal E. coli [24, 25]. Indigenous vaginal lactobacilli produce H2O2 and lactic acid which contributes to lowering vaginal pH which thus inhibits the growth of pathogenic bacteria, such as E. coli, and may ultimately reduce the risk of such organisms colonizing the urinary tract.

Pathogenesis

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The pathogenicity of UTI associated bacteria is based on their ability to attach, colonize, and survive in the urinary tract environment. UPEC strains, the most common pathogens for UTI, mainly enter the urogenital tract from the gut via fecal-perineal-urethral route [26]. UPEC strains possess several virulence factors, such as adhesins, toxins, iron acquisition factors, lipopolysacharide and capsules, that contribute to UTI pathogenesis. One of the main disease-causing mechanisms for UPEC is based on its adherence to mannosylated protein components called uroplakins on the bladder epithelium (Fig. 1) [2, 3]. This binding occurs via the FimH tip of the type I pili adhesin of E. coli. The attachment activates signal cascades causing actin rearrangement, which ultimately leads to an internalization of the bacteria into the umbrella cells of the epithelium [7]. The vesicular UPECs can be recognized by the innate immune system within the cells and exported via exocytosis back to the bladder where they are exposed to neutrophils and destroyed. However, UPEC strains employ several strategies to evade the host immune system, which facilitates formation of intracellular bacterial communities (IBCs); this enables bacteria to multiply, mature and infect other cells [27, 28]. Furthermore, this can potentially lead to more severe infection or risk for recurrence as the pathogen might remain hidden inside the uroepithelial cells.

Treatment

UTIs are commonly treated with antibiotics but due to increasing development of multidrug resistant strains, there is a need for alternative and complementary remedies [29,30,31]. The most commonly prescribed antibiotics are sulfonamides, trimethoprim, fluoroquinolones, fosfomycin, and beta-lactams, but resistance to these drugs varies between 15 and 50% in Europe, limiting their use for severe infections [32]. The use of some antibiotics, such as amoxicillin, has been restricted for UTI owing to the development of antibiotic resistance [17]. An international study on antibiotic susceptibility patterns performed in 17 European countries including 4734 women with acute uncomplicated UTI showed that 42% of the E. coli associated UTIs were resistant to one or more antibiotics. From the 12 used antimicrobials, the resistance was the highest for ampicillin (29.8%) and sulfamethoxazole (29.1%). Antibiotic resistance was relatively common also to trimethoprim (14.8%), trimethoprim/sulfamethoxazole (14.1%) and nalidixic acid (5.4%). Regional differences existed as in Spain and Portugal, antibiotic resistance was higher compared with the Nordic countries and Austria [33]. Another study performed in the US/Canada involving 40 clinical centers showed that E. coli resistance to ampicillin was 37.7, 21.3% to trimethoprim/sulfamethoxazole, 5.5% to ciprofloxacin, 5.1% to levofloxacin and 1.1% to nitrofurantoin [34]. Antibiotic resistance of UPEC has also been shown to be a prominent threat in Asia-Pacific regions [35, 36].

The family of Enterobacteriaceae (incl. E. coli) has acquired plasmids containing genes for extended-spectrum of β-lactamases (ESBL). β-lactamases cleave the amide bonds of β-lactams, thus the ability to produce β-lactamases compromises the antibiotic treatments making β-lactams ineffective in both uncomplicated and complicated UTIs [37, 38]. Research shows that UPEC strains isolated from the elderly who suffer from rUTIs, are cell-wall deficient i.e. providing to these strains resistance to antibiotics targeting the bacterial cell walls [39]. The WHO has listed Enterobacteriaceae as one of the pathogen groups that should be prioritized for research owing to its resistance patterns specifically to the third generation cephalosporin (β-lactam) that affects UTI treatments [6].

In addition to the development of multi-resistant strains the use of antibiotics for UTI has other disadvantages. For instance, in 25-35% of the cases rUTI occurred within 6 months of the first antibiotic treatment [40, 41] and in 44% of the cases within 12 months [10, 42]. Furthermore, repetitive use of antibiotics disturbs the indigenous microbiota especially in the gastrointestinal tract and vagina, and their use is often associated with unpleasant side effects such as nausea, vomiting, diarrhea, headaches, and skin rash. Thus, a search for alternative approaches to be used especially as a prophylactic in rUTIs is necessitated. Among the most commonly proposed natural alternatives is the daily intake of cranberries and/or D-mannose [31].

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